ABSTRACT (30 Lines Max) Objective: To develop and evaluate a safe, rapid, and functional three-dimensional (3D) pediatric neuroimaging modality based on photoacoustic computed tomography (PACT). Significance: Neuroimaging technologies are playing an increasingly important role in the initial detection and subsequent monitoring of a wide range of brain diseases and injuries in children. Such applications include detection and management of traumatic brain injury (TBI) and tumors, the assessment of risk of stroke in children with sickle cell disease, and imaging the preterm children brain, to name only a few. However, the available imaging methods possess significant shortcomings. For example, repeated X-ray CT studies remains controversial for the long-term effects of radiation exposure. MRI requires sedation due to its low imaging speed, which poses safety risks. Diffuse optical tomography suffers from inherently low spatial resolution. Rationale: We propose to develop a 3D PACT neuroimaging modality that would circumvent the limitations of existing methods and fill an important void left by the available techniques. PACT can exploit the strong optical absorption contrast of diseased or damaged brain tissues based on endogenous hemoglobin at high spatial resolution at depths. Its specific advantages over existing high-resolution pediatric neuroimaging modalities include: 1) measurement of injury information (anatomical and functional) that is complementary to that revealed by existing methods; 2) rapid imaging without need for sedation at bedside or in operating rooms; 3) use of non-ionizing radiation; and 4) relatively low-cost. Challenges: While widely thought to be impossible, our team has recently established the technical feasibility of transcranial PACT, promising enormous potential for pediatric imaging applications. However, several engineering challenges remain to be solved in order to translate this technology to a clinical setting. For example, a system must be designed that can rapidly image an unsedated infant with minimal motion artifacts. The imaging system must permit approximately uniform light delivery to the brain and allow for full- view acoustic detection. Additionally, specialized image reconstruction methods must be developed that can compensate for distortions in the measured PACT data due to the skull. Solutions: Our innovative research plan will result in a PACT imager that circumvents these challenges and will result in a highly effective and safe pediatric neuroimaging modality. The following specific aims have been designed to accomplish this. Aim 1: To develop a pediatric transcranial PACT imager. Aim 2: To develop PACT image reconstruction algorithms for use with the imager. Aim 3: To validate the proposed imaging system via computer simulations and physical phantoms. Aim 4: To validate the proposed imaging system using human subjects in vivo.